RT Journal Article
SR Electronic
T1 Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 616
OP 626
DO 10.1136/gutjnl-2020-323153
VO 71
IS 3
A1 Camille Péneau
A1 Sandrine Imbeaud
A1 Tiziana La Bella
A1 Theo Z Hirsch
A1 Stefano Caruso
A1 Julien Calderaro
A1 Valerie Paradis
A1 Jean-Frederic Blanc
A1 Eric Letouzé
A1 Jean-Charles Nault
A1 Giuliana Amaddeo
A1 Jessica Zucman-Rossi
YR 2022
UL http://gut.bmj.com/content/71/3/616.abstract
AB Objective Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features.Design A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping.Results Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes (TERT, TP53, MYC) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis.Conclusion Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.Data are available in a public, open access repository. The sequencing data of the LICA-FR cohort reported in this paper have been deposited to the European Genome-phenome Archive (EGA) database (RNA-seq fastq files accessions (EGAS00001001284), (EGAS00001002879), (EGAS00001003310), (EGAS00001003837) and (EGAS00001004629); WES bam files accessions (EGAS00001000217), (EGAS00001001002), (EGAS00001003063), (EGAS00001003130), (EGAS00001003837) and (EGAS00001004629); WGS bam files accessions (EGAS00001000706), (EGAS00001002408), (EGAS00001002888), (EGAS00001003063), (EGAS00001003837) and (EGAS00001004629), through the International Cancer Genome Consortium (ICGC) data access committee. Data are available for reuse and can be consulted at the following address: https://ega-archive.org/studies/EGASxxx with access permission from ICGC Data Access Compliance Office.